Synthesis of enantiopure, axially chiral, Cα-tetrasubstituted α-amino acids with binaphthyl-based crowned side chains and 3D-structural analysis of their peptides

The syntheses of the terminally protected, crowned, Cα-tetrasubstituted α-amino acids with only axial chirality, the two diastereomers Boc-(S)-Bip[(R)-Binol-22-C-6]-OMe and Boc-(R)-Bip[(R)-Binol-22-C-6]-OMe, and their respective enantiomers Boc-(R)-Bip[(S)-Binol-22-C-6]-OMe and Boc-(S)-Bip[(S)-Binol-22-C-6]-OMe, all derived from 2′,1′:1,2; 1″,2″:3,4-dibenzcyclohepta-1,3-diene-6-amino-6-carboxylic acid (Bip), were performed by bis-alkylation with cyclization of racemic (R+S)-Boc-[HO]2-Bip-OMe, possessing two phenolic OH groups at the 6,6′-positions of the biphenyl frame of Bip, using (+)-(R)- and (−)-(S)-Binol[(OCH2CH2)2OTs]2 (2,2′-bis[5-tosyloxy-3-oxa-1-pentyloxy]-1,1′-binaphthyl), respectively, as the alkylating agent followed by chromatographic separation. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with either l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analyses by FTIR absorption and NMR suggest that these peptides preferentially adopt folded secondary structures.

Graphical abstractBoth pairs of isomers (R)/(S)-Bip[(R)/(S)-Binol-22-C-6] of a new, only axially chiral, Cα-tetrasubstituted α-amino acid with binaphthyl-based crowned side chains, have been synthesized and resolved in an enantiopure state. Two series of terminally protected model peptides to the hexamer level, containing the (R)-Bip[(S)-Binol-22-C-6] residue at i and i+3 positions of the sequence, combined with l-Ala or l-Ala/Aib, were synthesized by solution methods. Their 3D-structural analysis by FTIR absorption and NMR suggests that they preferentially adopt folded secondary structures.Figure optionsDownload full-size imageDownload as PowerPoint slide